Intervention Trials in Persons at Increased Genetic Risk of Cancer

针对癌症遗传风险增加人群的干预试验

• 批准号: 8938240
• 负责人: MARK H GREENE
• 金额: $ 53.47万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8938240
• 关键词: Algorithms; BRCA1 gene; BRCA2 gene; Behavioral; Benign; Bilateral; Blinded; Breast; British Columbia; CA-125 Antigen; Cancer Genetics Network; Candidate Disease Gene; Characteristics; Chemoprevention; Chicago; Clinical Data; Clinical Oncology; Collaborations; Computers; Counseling; DNA; Data; Data Set; Databases; Decision Making; Detection; Development; Diagnosis; Duct (organ) structure; Early Diagnosis; Enrollment; Epithelial Cells; Estrogens; Family; Future; General Population; Genes; Genetic Risk; Genotype; Goals; Gynecologic Oncology Group; Hereditary Malignant Neoplasm; High Risk Woman; Hormones; Hysterectomy; Image; Individual; Intervention; Intervention Studies; Intervention Trial; Irrigation; Journals; Learning; Lesion; Life Style; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mammographic Density; Mammography; Manuscripts; Measures; Mediation; Medical; Messenger RNA; Methods; Methylation; Modeling; Molecular; Mucous Membrane; Mutation; Natural History; Neoplasms; Oncogenes; Operative Surgical Procedures; Ovarian; Ovarian hormone; Participant; Pathogenesis; Pathology; Patients; Pelvis; Performance; Peritoneal Neoplasms; Persons; Phenotype; Pilot Projects; Postmenopause; Premenopause; Preparation; Prevalence; Procedures; Province; Psychosocial Assessment and Care; Publications; Published Comment; Publishing; Quality of life; Reagent; Recruitment Activity; Relative (related person); Reporting; Research; Research Design; Research Personnel; Research Project Grants; Risk; Risk Reduction; Salpingo-Oophorectomy; Sampling; Screening for Ovarian Cancer; Screening for cancer; Series; Serous; Serum; Staging; Stratification; Surface; Surgical Pathology; Test Result; Testing; Time; Tissues; Translational Research; Transvaginal Ultrasound; Tubal Excisions; Tubal Ligation; Universities; Validation; Woman; arm; base; cancer risk; cohort; follow-up; genome wide association study; high risk; improved; intraepithelial; malignant breast neoplasm; mutation carrier; novel; ovarian cancer prevention; prospective; repository; risk perception; screening; tool; uptake

The National Ovarian Cancer Prevention and Early Detection Study [CAS 7210] among women at increased genetic risk of ovarian cancer (aka GOG-199) is the cornerstone of CGB's intervention studies research portfolio. It is a non-randomized natural history study of risk-reducing salpingo-oophorectomy (RRSO) versus a novel ovarian cancer screening strategy (the ROCA algorithm). This study closed to new patient enrollment in November 2006, having accrued 2605 high-risk women (1029 surgery arm; 1576 screening arm). Prospective follow-up ended in November 2011, and the final analytic data base is now complete. Accomplishments to date include: (1) successfully completing subject accrual; (2) completing the research-based BRCA1/2 mutation testing for the 1,500 mutation-unknown study participants; (3) completing the central pathology review of 1037 risk-reducing salpingo-oophorectomy (RRSO) samples; (4) publishing a report detailing the rationale and design of the study, along with baseline characteristics of the women in each cohort; (5) developing a preliminary model of the factors which influence the choice of RRSO versus screening; (6) contributing 1,576 screening subjects to a published pooled analysis (with the Cancer Genetics Network: total = 4,000 subjects) of determinants of baseline CA-125 levels and of the performance characteristics of the ROCA algorithm, which demonstrated that pre-menopausal women should have an upper limit of normal cut-off=52, rather than 35 as customarily used; (7) creating a unique biospecimen repository for future translational research; and (8) negotiating a collaboration between GOG and CIMBA under which DNA and clinical data from our 1100 mutation carriers are being contributed to multiple pooled candidate gene association studies of BRCA-related breast and ovarian cancer risk, and two genome-wide association studies (GWAS), one for each BRCA gene. 32 published manuscripts have resulted from this collaboration, and an additional 7 are currently under review. Our Commentary proposing that bilateral salpingectomy might be a valuable ovarian cancer risk-reduction option has led to the development of a new GOG pilot study to test the feasibility of this approach in BRCA1/2 mutation carriers, and the Canadian province of British Columbia has implemented bilateral salpingectomy as a routine procedure in women undergoing benign hysterectomy and tubal ligation in its general population. A CIMBA manuscript describing what will be the definitive genotype/phenotype analysis of breast and ovarian cancer risk in 30,000 BRCA mutation carriers has been accepted for publication in JAMA, and data from another dozen candidate SNPs are in various stages of analysis and manuscript preparation. Our report describing that invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 GOG-09199 RRSOs (BRCA1 carriers=4.6%, BRCA2 carriers=3.5%, and non-carriers=0.5% (p=0.0006) will appear shortly in the Journal of Clinical Oncology. In multivariable models, positive BRCA1/2 mutation status (p=0.0056), postmenopausal status (p=0.0023) and abnormal CA-125 levels and/or transvaginal ultrasound examinations (p0.0001) were associated with detection of clinically-occult neoplasms at RRSO. These data provide the best current estimates of the prevalence of clinically-occult serous pelvic malignancy at the time of RRSO. Additional analyses are now underway related to (1) the performance characteristics of the ROCA ovarian cancer screening algorithm in the pooled GOG-199/CGN data set (manuscript ready for submission); (2) testing/validation of the medical decision-making model related to choice between surgery and screening; (3) a description of baseline quality of life by study arm; (4) blinded pathology review of RRSO surgical pathology material to determine intra- and inter-observation concordance related to the diagnosis of proliferative lesions in the fallopian tube mucosa; (5) analysis of the prospective risk of breast and ovarian cancer based on the prospective follow-up of this cohort; (6) the relationship between ovarian size and circulating ovarian hormone levels; and (7) a pilot study evaluating a novel method for collecting ovarian cancer surface epithelial cells as translational research reagents. Methylation and mRNA profiling are currently being performed in collaboration with colleagues at Johns Hopkins. Multiple biospecimen-based translational research projects are both underway and planned. The Breast Imaging Pilot Study in Women from BRCA Mutation-Positive Families reached its accrual goal of 200 women from BRCA1/2 mutation-positive families; prospective follow-up ended in February 2010. A published analysis of baseline mammographic density (MD) has revealed no differences between mutation carriers and low-risk women. Analyses of MRI volume in carriers versus non-carriers and correlations between with MD are nearing completion. Our digitized mammographic images were used in a just-published collaboration with investigators from the University of Chicago to identify various novel imaging characteristics that are strongly correlated with BRCA mutation status; these computer-derived features may improve radiographic breast cancer risk stratification relative to standard mammography. Our breast duct lavage (BDL) study in the largest cohort of BRCA mutation carriers yet reported led us to abandon BDL as a research/risk stratification tool. DNA samples from mutation-positive BI participants have been contributed to our collaboration with CIMBA. We have published pilot data documenting that femtogram quantities of estrogen metabolites are detectable in both NAF and BDL fluid, and demonstrated that circulating estrogens and estrogen metabolites are strongly and positively correlated when measured in both tissues. This suggests that future etiologic studies could utilize the more readily obtainable serum hormone levels as a reliable surrogate measure of exposure at the tissue level. Our most recent psychosocial study using the Breast Imaging Study patients revealed that false positive cancer screening test results were not associated with large increases in cancer risk perception, cancer worry or increased uptake of risk-reducing surgery. However, cancer-specific worry was an independent predictor of uptake of risk-reducing surgery; this domain warrants consideration when counseling high-risk women regarding risk-reducing interventions.

国家卵巢癌预防和早期检测研究[CAS 7210]在卵巢癌遗传风险增加的妇女中（又名GOG-199）是CGB干预研究组合的基石。这是一项降低风险的输卵管卵巢切除术（RRSO）与新型卵巢癌筛查策略（ROCA算法）的非随机自然史研究。该研究于2006年11月结束新患者入组，共纳入2605名高危女性（手术组1029名，筛查组1576名）。预期随访于2011年11月结束，最终的分析数据库现已完成。迄今为止的成就包括：(1)成功完成科目应计；(2)对1500名突变未知的研究参与者完成基于研究的BRCA1/2突变检测；(3)完成1037例降低风险的输卵管卵巢切除术（RRSO）样本的中心病理检查；(4)发表一份报告，详细说明研究的基本原理和设计，以及每个队列中女性的基线特征；(5)建立影响RRSO选择与筛查的因素的初步模型；(6)将1576名筛查对象纳入已发表的汇总分析（与癌症遗传学网络一起：总共= 4,000名受试者），分析基线CA-125水平的决定因素和ROCA算法的性能特征，结果表明，绝经前妇女的正常临界值上限应为52，而不是通常使用的35；(7)为未来的转化研究创建一个独特的生物标本库；(8)协商GOG和CIMBA之间的合作，根据该合作，来自我们1100个突变携带者的DNA和临床数据将用于BRCA相关乳腺癌和卵巢癌风险的多个候选基因关联研究，以及两个全基因组关联研究（GWAS），每个BRCA基因一个。这一合作产生了32份已发表的手稿，另外7份目前正在审查中。我们的评论提出，双侧输卵管切除术可能是一种有价值的降低卵巢癌风险的选择，这导致了一项新的GOG试点研究的发展，以测试这种方法在BRCA1/2突变携带者中的可行性，加拿大不列颠哥伦比亚省已将双侧输卵管切除术作为其普通人群中接受良性子宫切除术和输卵管结扎的妇女的常规手术。一篇描述3万名BRCA突变携带者乳腺癌和卵巢癌风险的决定性基因型/表型分析的CIMBA论文已被接受发表在《美国医学会杂志》上，另外12个候选snp的数据正处于不同的分析和论文准备阶段。我们的报告描述了966例GOG-09199 RRSOs中有25例（2.6%）检测到浸润性或上皮内卵巢/输卵管/腹膜肿瘤(BRCA1携带者=4.6%，BRCA2携带者=3.5%，非携带者=0.5% （p=0.0006）将很快发表在《临床肿瘤学杂志》上。在多变量模型中，BRCA1/2阳性突变状态（p=0.0056）、绝经后状态（p=0.0023）、CA-125水平异常和/或经阴道超声检查（p0.0001）与RRSO临床隐匿性肿瘤的检测相关。这些数据提供了目前对RRSO时临床隐匿性浆液性盆腔恶性肿瘤患病率的最佳估计。目前正在进行的其他分析涉及：(1)ROCA卵巢癌筛查算法在GOG-199/CGN汇总数据集中的性能特征（手稿准备提交）；(2)检验/验证与手术与筛查选择相关的医疗决策模型；(3)各组基线生活质量的描述；(4)对RRSO手术病理资料进行盲法病理复习，以确定与输卵管粘膜增生性病变诊断相关的观察内及观察间一致性；(5)基于本队列前瞻性随访的乳腺癌、卵巢癌前瞻性风险分析；(6)卵巢大小与卵巢循环激素水平的关系；(7)一项评估收集卵巢癌表面上皮细胞作为转化研究试剂的新方法的中试研究。甲基化和mRNA分析目前正在与约翰霍普金斯大学的同事合作进行。多个基于生物标本的转化研究项目正在进行和计划中。BRCA突变阳性家庭女性乳腺影像学试点研究达到了200名BRCA1/2突变阳性家庭女性的累积目标；预期随访于2010年2月结束。一项已发表的基线乳房x线摄影密度（MD）分析显示，突变携带者和低风险女性之间没有差异。携带者与非携带者的MRI体积分析以及与MD之间的相关性已接近完成。我们的数字化乳房x线摄影图像被用于与芝加哥大学的研究人员合作，以确定与BRCA突变状态密切相关的各种新的成像特征；与标准乳房x线摄影相比，这些计算机衍生的特征可以改善x线摄影的乳腺癌风险分层。我们在迄今报道的BRCA突变携带者的最大队列中进行的乳腺导管灌洗（BDL）研究使我们放弃将BDL作为研究/风险分层工具。突变阳性BI参与者的DNA样本已提供给我们与CIMBA的合作。我们发表的试点数据表明，在NAF和BDL液中均可检测到雌激素代谢物的飞图量，并证明在两种组织中测量循环雌激素和雌激素代谢物时存在强烈的正相关。这表明，未来的病因学研究可以利用更容易获得的血清激素水平作为可靠的替代测量暴露在组织水平。我们最近对乳房成像研究患者进行的社会心理研究显示，癌症筛查结果假阳性与癌症风险认知、癌症担忧或降低风险手术的增加无关。然而，癌症特异性担忧是接受降低风险手术的独立预测因素；在对高危妇女进行降低风险干预的咨询时，这一领域值得考虑。